Highlights from Recent Cancer Literature
Journal: Cancer Research (2011)

Li F, Ravetch JV. Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 2011;333:1030–4.Monoclonal antibodies form the backbone of targeted cancer therapeutics, whether designed for depletion of neoplastic cells (e.g., rituximab), blocking pathways necessary for tumor growth (e.g., trastuzumab and bevacizumab), or more recently unleashing the immune system via blockade of immunosuppressive pathways that limit a cytotoxic response (ipilimumab). Mirroring this latest approach are attempts to enhance the function of antigen-presenting cells (APC), including dendritic cells (DC), with the hope that this approach will more selectively direct T-cell responses against tumors. One of the leading candidates for this approach has been development of antibodies against CD40, a costimulatory molecule expressed by APCs. Li and Ravetch now show that the immunoglobulin (Ig) subtype of anti-CD40 antibodies is a critical mediator of therapeutic efficacy in several implantable tumor models through differential binding to Fc receptor isoforms. Using a DC-targeted vaccination approach, they found that anti-CD40 treatment failed to promote induction of a T-cell response in mice deficient for the inhibitory Fc receptor (FcγRIIB), but that this occurred normally in mice lacking activating Fc receptors. Because IgG1 isotypes selectively bind to FcγRIIB, whereas IgG2a isotypes most efficiently induce antibody dependent cellular cytotoxicity (ADCC) through engagement of FcγRIV, the authors compared the ability of each of these anti- CD40 isotypes to limit growth in CD40-negative tumor models. Consistent with their original observations, they found that only the IgG1 isotype acted as an adjuvant with DC vaccination to limit tumor growth. Although ADCC against human lymphomas has already been described, in this instance the authors observed therapeutic efficacy in CD40-positive tumor models only with the IgG1 anti-CD40 antibody, even in the absence of vaccination. These findings may prove critical for design of therapeutic antibodies that engage productive antitumor immune responses.Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 2011;20:143–57.Ependymoma is a relatively rare but lethal brain tumor that is incurable in nearly half of cases. Ependymal cells represent a proliferative population that lines the walls of the ventricular system, with transformation of ependymal cells in the forebrain more common in adults (supratentorial tumors), and transformation in the hindbrain occurring most commonly in childhood ependymoma. Sadly, these tumors are resistant to chemotherapy. Moreover, a paucity of genetic information has limited use of targeted agents in this disease. To clarify molecular distinctions between posterior fossa ependymomas of childhood, Witt and colleagues collaborated to generate and analyze separate German and Canadian cohorts totaling 17 hindbrain ependymomas. Transcriptomal classification identified 2 groups of tumors, with aggressive group A tumors occurring in younger children, in males, in instances of relative genomic stability, and in instances of decreased genomic instability, as compared with group B tumors. The authors showed that these 2 tumor types were distinguished by standard immunohistochemical stains, enabling risk stratification and intensified therapy for those children at highest risk.Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG, Harris BT, et al. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 2011;333:1039–43.Genomic instability is common in solid tumors, but the molecular basis for this phenomenon is poorly understood. Solomon and colleagues analyzed single-nucleotide peptide arrays of human cancers, identifying a deletion on the X chromosome that included the STAG2 gene, a subunit of the cohesion complex, required for cohesion of sister chromatids afterDNAreplication. Loss of STAG2 by Western blot occurred in 3 of 21 glioblastoma tumors, 5 of 9 Ewing sarcomas, and 1 of 10 melanoma cell lines examined. To evaluate functional consequences of STAG2 loss, the authors corrected endogenous STAG2 mutant allele in 2 aneuploid glioblastoma cell lines and mutated the gene in a near diploid human colorectal cell line. STAG2 proficiency was associated with nearly perfect sister chromatid cohesion, which was lost in STAG2- deficient cells. These data suggest a role for cohesion in maintaining genomic stability, and for loss of a single copy of STAG2, an X-linked gene, leading to aneuploidy in cancer.Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 2011;146:1–13.The cell of origin for glial brain tumors remains an area of active investigation. Results from mouse model studies suggest that such cells may reside in the subventricular zone, an area of ongoing neurogenesis. In addition, specific subtypes of glial tumors have been shown in both mouse and human studies to arise from oligodendroglial precursor cells (OPC), an abundant and proliferative population that resides primarily in white matter. Liu and colleagues used genetic mosaic analysis to generate mice carrying a limited number of cells deleted for the tumor suppressor genes p53 and Nf1, both of which have previously been implicated in human glioma. These studies validate earlier findings pointing to OPCs as cells of origin in glial malignancies driven by loss of Nf1 and p53.Winkler AE, Brotman JJ, Pittman ME, Judd NP, Lewis JS Jr, Schreiber RD, et al. CXCR3 enhances a T-cell-dependent epidermal proliferative response and promotes skin tumorigenesis. Cancer Res 2011;71:5707–16.Accumulating evidence indicates that cells of the immune system play critical roles as regulators of malignancy due to their differential abilities to regulate pro- and/or antitumor immunity. Examination of genetically modified or chemically induced mouse models susceptible to de novo tumor development, where selective components of the immune system or immune response have been deleted or modified, has provided important clues regarding the functional significance of specific immune response programs as regulators of tumor development. Although the important role of T cells in preventing cancer is well known, a remaining question is why the incidence of methylcholantrene (MCA)-induced tumors in mice lacking some T cell subsets is enhanced, whereas the same mice treated with 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) show reduced susceptibility to tumor development. Recent findings from Winkler and colleagues may provide an answer. These authors found that the chemokine receptor CXCR3 plays an important role in infiltrating immune cells following DMBA/TPA treatment, but no role following MCA exposure. Using CXCR3-deficient mice and both carcinogenesis protocols, they found that CXCR3 promoted tumor development in the DMBA/TPA model but had no role in MCA carcinogenesis or in rejection of transplantable, immunogenic tumor cell lines. CXCR3 was found to play an important role in regulating epidermal proliferation in response to DMBA/TPA, an effect likely due to CXCR3 activity in CD3+ T cells.Desch AN, Randolph GJ, Murphy K, Gautier EL, Kedl RM, Lahoud MH, et al. CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen. J Exp Med 2011;208:1789–97.To extend durable tumor repression following common cytotoxic therapy, novel therapeutic strategies are needed that also foster productive adaptive antitumor immunity. Dendritic cells (DC) are antigen-presenting cells (APC) responsible for T-cell priming (T cells are a vital component of adaptive immunity against tumors). Based on the concept that antitumor immunity can be boosted, first-generation DC vaccines were developed and have now shown positive clinical proof-of-concept results. Details on the functional diversity of distinct DC subsets have expanded, with the recognition that some subsets of DCs possess enhanced capability to prime T cells, and/or selectively take up antigens. Splenic CD8+ and nonlymphoid tissue CD103+ DCs, for example, are professional cross-priming DCs that share many properties, including developmental regulation by Flt3 and expression of transcription factors Irf8 and Batf3. Recent data indicate that apoptotic cells are selectively efferocytized (DC and macrophage phagocytosis) for T-cell cross priming by these DC subsets. Desch and colleagues now report that pulmonary CD103+ DCs also selectively efferocytize apoptotic cells and present antigens to CD8+ T cells in afferent lymphatics, in addition to expressing high levels of toll-like receptor (TLR)-3. TLR agonists have been found to further enhance T-cell priming by DCs. Thus, it is reasonable to speculate that TLR agonists, in combination with CD103+-based DC vaccines, may improve clinical efficacy of cytotoxic therapy by boosting adaptive immunity to cancer.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.